In recent years, bone tissue engineering has emerged as a promising solution to the limitations of current gold standard treatment options for bone related-disorders. Bone tissue engineering relies on a scaffold design that mimics the extracellular matrix, providing an architecture that guides the natural bone regeneration process. Incorporation of growth factors into such scaffolds has been of particular interest due to their ability to enhance cell recruitment and promote osteogenic differentiation and angiogenesis. Bone regeneration is a multi-phase process with different growth factors acting in each phase. Bone regeneration can be enhanced by delivering multiple growth factors in sequence or combination; however this requires precise temporal control to ensure physiologically relevant profiles. Other challenges in growth factor delivery include the rapid loss in bioactivity before the molecules reach the site of injury and the inability of molecules to remain at the site of injury for extended periods of time. Here, we have developed a two-phase system for the sustained delivery of growth factors. In this system, growth factors are encapsulated in nanoparticles, which are then covalently bound to a degradable scaffold. These nanoparticles incorporate a hydrolytically degradable crosslinker that can be tuned to enable the desired sustained release profile of a given growth factor. By incorporating chemically-conjugated nanocarriers, our two-phase system protects the growth factor from rapid degradation while also improving the release kinetics. The nanoparticles were synthesized using an aqueous, one-pot UV-initiated emulsion polymerization and were comprised from methyl methacrylate, methacrylic acid, and a customizable poly(lactic acid)-b
-poly(ethylene glycol) dimethacrylate crosslinking agent. Tunability of the nanoparticle degradation was investigated through systematic variation of PLA and PEG chain length in the crosslinker. The physical properties of the resulting nanoparticles were compared using dynamic light scattering, zeta potential, FTIR, and NMR to elicit the influence of polymer composition on swelling ratio, surface charge, and degradation kinetics. The release profiles were analyzed using trypsin as a model for bone morphogenetic proteins. Ultimately, our work demonstrates that the incorporation of two-phase systems consisting of growth factor-loaded nanoparticles embedded into scaffolds shows great promise, both by providing sustained release over a therapeutically relevant timeframe and the potential to sequentially deliver multiple growth factors.
Acknowledgements: The work was supported in part by a grant from the National Institutes of Health (R01-EB-022025) and the Cockrell Family Regents Chair. A.M.W. was also supported in part by a National Science Foundation Graduate Research Fellowship (DGE-1610403), the S.E.S.H.A. Endowed Graduate Fellowship in Engineering, and the Philanthropic Educational Organization Scholar Award. M.S. was also supported in part by a Thrust 2000 Graduate Fellowship in Engineering.